Switching on Supramolecular Catalysis via Cavity Mediation and Electrostatic Regulation

Article abstract of DOI:10.1002/anie.201606847

Synthetic supercontainers constructed from divalent metal ions, carboxylate linkers, and sulfonylcalix[4]arene-based container precursors exhibit great promise as enzyme mimics that function in organic solvents. The capacity of these artificial hosts to catalyze Knoevenagel condensation can be switched on when the aldehyde substrate possesses a molecular size and shape matching the nanocavity of the supercontainers. In contrast, little reactivity is observed for other aldehydes that do not match the binding pocket. This substrate-dependent catalytic selectivity is attributed to the Br?nsted acidity of the metal-bound water molecules located inside the nanocavity, which is amplified when the size/shape of the aldehyde substrate fits the binding cavity. The electrostatic environment of the binding cavity and the Br?nsted acidity of the supercontainer can be further modulated using tetraalkylammonium-based regulators, leading to higher reactivity for the otherwise unreactive aldehydes.

Full text of DOI:10.1002/anie.201606847

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201606847
German Edition: DOI: 10.1002/ange.201606847
Supramolecular Catalysis
Switching on Supramolecular Catalysis via Cavity Mediation and
Electrostatic Regulation
Yupu Qiao, Long Zhang,* Jia Li, Wei Lin,* and Zhenqiang Wang*
Abstract: Synthetic supercontainers constructed from divalent
metal ions, carboxylate linkers, and sulfonylcalix[4]arene-
based container precursors exhibit great promise as enzyme
mimics that function in organic solvents. The capacity of these
artificial hosts to catalyze Knoevenagel condensation can be
switched on when the aldehyde substrate possesses a molecular
size and shape matching the nanocavity of the supercontainers.
In contrast, little reactivity is observed for other aldehydes that
do not match the binding pocket. This substrate-dependent
catalytic selectivity is attributed to the Brønsted acidity of the
metal-bound water molecules located inside the nanocavity,
which is amplified when the size/shape of the aldehyde
substrate fits the binding cavity. The electrostatic environment
of the binding cavity and the Brønsted acidity of the super-
container can be further modulated using tetraalkylammo-
nium-based regulators, leading to higher reactivity for the
otherwise unreactive aldehydes.
cules has emerged as a promising approach to mimicking
enzymatic catalysis.[4] Container molecules are well suited for
this task, as they possess chemically tunable nanocavity that
can imitate the microenvironment of enzyme binding pockets
and harness multiple non-covalent interactions in a synergistic
manner.[5] However, despite the impressive progress made in
the last decades, designing enzyme-like, cavity-mediated
supramolecular catalysis remains generally challenging,
which is due in no small measure to the prevalence of
product inhibition.[6] Furthermore, the ability to regulate
catalytic processes using small molecules or ions via an
allosteric[7] or electrostatic[8] mechanism, a strategy master-
fully employed by Nature to modulate enzyme functions, has
been relatively elusive to attain in synthetic systems.[9] Herein,
we discuss how these critical issues can be addressed in a new
class of synthetic supercontainers, wherein their ability to
promote supramolecular catalysis can be switched on through
selective recognition of the substrate size/shape and electro-
static modulation of the binding pocket via cationic regula-
tors.
E
nzymes are Natureꢀs catalysts par excellence. By virtue of
their remarkable substrate selectivity, superior catalytic
efficiency, and mild operational conditions, enzymes have
provided the ultimate inspiration for researchers interested in
catalyst design.[1] Several critical elements, including precise
organization of the substrate within the close proximity of the
binding pocket and well-tuned electrostatic environment of
the active site, are widely recognized as key to the ability of
enzymes to accelerate otherwise sluggish chemical reactions
in an astonishingly efficient manner.[2] Chemists have long
endeavored to emulate such elegant efficacy in synthetic
catalytic systems, particularly through rational design of
artificial constructs using supramolecular chemistry princi-
ples.[3] Indeed, supramolecular catalysis by container mole-
We recently reported a unique family of coordination
containers, termed metal–organic supercontainers (MOSCs),
which were obtained from the assembly of sulfonylcalix-
[4]arene-based container precursors,[10] divalent metal ions,
and carboxylate linkers of various shapes.[11] For example, the
reaction of p-tert-butylsulfonylcalix[4]arene (TBSC), CoII or
NiII, and an angular semi-flexible dicarboxylate linker such as
4,4’-methylenedibenzoic acid (H2L1) or 4,4’-iminobis(methy-
lene)-dibenzoic acid (H2L2), gave rise to two members of the
type IV MOSC family, designated here as MOSC-1 and
MOSC-2, respectively (Scheme 1; Supporting Information,
Scheme S1).[11e] These type IV MOSCs possess both endo and
exo cavities and thus exhibit the trademark multi-pore
architecture also observed in other prototypes of MOSCs.
[*] Dr. Y. Qiao, Dr. J. Li, Prof. Dr. Z. Wang
Department of Chemistry, University of South Dakota
414 East Clark Street, Churchill-Haines Laboratories, Room 115
Vermillion, SD 57069-2390 (USA)
E-mail: Zhenqiang.Wang@usd.edu
Dr. L. Zhang
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing, 100190 (China)
E-mail: zhanglong@iccas.ac.cn
Dr. W. Lin
Department of Chemistry, University of Minnesota
Minneapolis, MN 55455 (USA)
E-mail: antifreezeprotein@gmail.com
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201606847.
Scheme 1. Assembly of supercontainer MOSC-1.
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The cylindrically-shaped type IV MOSCs can be described as
consisting of four dicarboxylate linkers bridging two tetranu-
clear complexes,[12] each of which contains four metal ions
coordinating to one TBSC unit, four carboxylate groups, and
one presumed m4-H2O species (Scheme 1; Supporting Infor-
mation, Scheme S1).
selectivity with regard to the aldehyde was clearly observed,
as evidenced by the substantially lower yield of 1-naphthal-
dehyde (1 f, 34%) than that of 1b (92%) under otherwise
identical conditions. A similarly moderate yield (44%) was
also noted for 9-anthracenecarboxaldehyde (1g), a close
structural analogue of 1 f. This interesting contrast of
reactivity between the two groups of substrates, which
orientate their aldehyde moiety in a manner that can be
described as “parallel” and “perpendicular” to their aromatic
backbone, respectively (Table 1,entries a–e vs. f and g;
Supporting Information, Scheme S2), suggests that the alde-
hyde substrate binds to the MOSC in a spatially defined
manner, likely driven by the cylindrical shape of the MOSC
endo cavity dictating the specific host–guest binding geometry
(see below).
To interrogate this intriguing trend of reactivity, we
examined MOSC-1, a non-amine analogue of MOSC-2, and
discovered that, not so surprisingly, it showed negligible
catalytic activity towards the majority of the aldehydes
examined above (Table 1), owing to its lack of Lewis basicity.
Strikingly though, one particular substrate, namely 1e, stood
out as a notable exception. The Knoevenagel condensation of
1e with 2a was effectively catalyzed by MOSC-1, giving rise
to a decent yield of 67% using 1 mol% loading of the
supramolecular catalyst. While the base-promoted b-hydroxy
or iminium intermediate constitutes the most common
reaction mechanism, this unexpected result and unusual
substrate selectivity prompted us to re-evaluate the under-
pinning of the MOSC-catalyzed reactions. Several previous
reports suggested that a Brønsted acid can also facilitate the
Knoevenagel condensation through protonation of the alde-
hyde group.[15] Although acid-catalyzed Knoevenagel reac-
tions are generally rare presumably as a result of the
propensity of the acid catalyst to neutralize the deprotonated
nucleophile, we reason that such an undesired quenching
effect may be avoided if the Brønsted acid is properly
immobilized in a porous matrix, as implied by the study of
Saravanamurugan et al.[15a]
Previous preliminary findings suggested that, owing to its
Lewis basicity derived from its secondary amine group,
MOSC-2 exhibited excellent catalytic activity for the Knoe-
venagel condensation[13] involving the nucleophilic addition
of malononitrile (2a) to 2-naphthaldehyde (1b).[11e] This
supramolecular reactivity was consistent with the generally
accepted reaction mechanism, which typically involves an
amine base promoting the formation of a b-hydroxy inter-
mediate and/or an iminium intermediate.[14] Follow-up studies
revealed that MOSC-2 also effectively catalyzed the reaction
for a range of other aldehydes (Table 1). Interestingly, there
appeared to be no direct correlation between the reactivity
and the aldehyde size, since bulkier 1-pyrenecarboxaldehyde
(1e) and smaller 2-naphthaldehyde (1b) both gave a similar,
near-quantitative yield (95% vs. 92%). In contrast, a shape
Table 1: Yields for Knoevenagel reactions of malononitrile with various
aldehydes, catalyzed by MOSC-1, MOSC-1/TMA+ClÀ, and MOSC-2.[a]
Entry
Aldehyde
Yield [%]
MOSC-1/
TMA+ClÀ
MOSC-
1
MOSC-
2
a
1a
1b
7
5
46
62
67
92
b
In light of this scenario, we propose the following reaction
mechanism (Scheme 2) and attribute the catalytic activity of
MOSC-1 towards 1e to its Brønsted acidity originating from
CoII-bound m4-H2O. Specifically, the substrates (1e and 2a)
bind to the endo cavity of MOSC-1, and the m4-H2O located
inside then protonates the carbonyl group of 1e, activating the
aldehyde substrate and enhancing its electrophilicity with 2a.
The so-formed b-hydroxy intermediate undergoes dehydra-
tion and gives rise to the final alkenyl product, which is
released from the cavity owing to its relative bulkiness. The
substrate selectivity with regard to 1e can be rationalized on
the basis of a lock-and-key type match between MOSC-1 and
1e. The relatively weak Brønsted acidity of the m4-H2O means
that MOSC-1 does not readily protonate and activate an
aldehyde unless the substrate possesses a suitable molecular
size and shape to fit inside the cavity and allow its aldehyde
moiety to be pre-organized within the close proximity of the
active site.
c
d
e
1c
1d
1e
1
2
33
34
55
89
81
95
67
f
1 f
3
3
50
40
34
44
g
1g
The proposed mechanism was supported by several lines
of considerations. A particularly enlightening evidence came
from our density functional theory (DFT) calculation, which
[a] TMA+ =Tetramethylammonium cation; 6 mol% of TMA+ClÀ was
used.
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reaction takes place inside the MOSC endo cavity, as the
impeded reactivity of 2b in the presence of MOSC-1 can be
attributed to its higher steric bulk within the restricted
nanoenvironment of the endo cavity.
The most profound implication of the proposed mecha-
nism was the realization that the catalytic efficacy of MOSC-
1 could be regulated by cations serving as electrostatic
effectors. A conceivable rationale was that a suitable cation
may enhance the Brønsted acidity of the m4-H2O through
stabilizing the deprotonated OHÀ anion. This reasoning was
indeed experimentally confirmed by adding the chloride salt
of tetramethylammonium (TMA+) cation to the MOSC-
1 promoted reactions involving 2a and various aldehydes. In
the presence of TMA+, the otherwise unreactive aldehydes
examined above exhibited a substantially higher reactivity
and readily underwent the Knoevenagel reaction (Table 1).
Interestingly, unlike these smaller aldehydes, 1e actually
showed a slightly lower yield with TMA+ than without it
(55% vs. 67%). Close examination of the reaction kinetics
nevertheless revealed that the combination of MOSC-1 and
TMA+ did significantly enhance the reaction rate of 1e in the
initial stage of the reaction (Figure 1). Without TMA+, the
Scheme 2. Proposed mechanism for the Knoevenagel condensation
catalyzed by MOSC-1.
indicated that 1e was indeed capable of binding to the endo
cavity of MOSC-1 and pre-aligning its carbonyl group near
the active site (Supporting Information, Figure S4a). The
substrate recognition was achieved partly through the m4-H2O
molecule hydrogen-bonding with the carbonyl oxygen of 1e
À
(O···O 2.73 ꢁ). Multiple C H···p interactions were also
abundantly present between the phenyl moieties of the
MOSC endo cavity and the pyrene backbone of 1e. These
[16]
À
C H···p interactions, while individually weak, contributed
in a concerted manner to organizing the substrate in its pre-
reactive conformation. It is not difficult to envisage that
À
similar synergistic C H···p interactions may have also been
implicated in the MOSC-2 system and accounted for its shape
selectivity discussed above. Specifically, the carbonyl groups
of the perpendicular aldehydes were likely forced to point
away from the m4-H2O center as a result of the preferred
Figure 1. Reaction kinetics of the Knoevenagel condensation of 1-
pyrenecarboxaldehyde with malononitrile, in the presence of MOSC-
1 (black), MOSC-1/TMA+ (red), and TMA+ (blue), respectively.
À
orientation of the C H···p interactions, rendering these
aldehydes less effectively activated. Additional DFT calcu-
reaction consisted of an induction period, in which little
product was formed in the first 35 hours. The product
generation rapidly accelerated after this period, quickly
reaching saturation within about 5 hours. In contrast, the
addition of TMA+ (6 equiv to MOSC-1) to the reaction
mixture eliminated the induction period and the product
formation became apparent almost immediately. It is worth
noting that TMA+ alone did not catalyze the Knoevenagel
reaction. This thus suggests that to promote the reaction,
TMA+ must partner with MOSC-1, most likely through
binding to the MOSC endo cavity via electrostatic interac-
tions.[18] The importance of the endo cavity on the catalysis
was further illustrated by the lack of Knoevenagel reactivity
observed for 1e when MOSC-1 was substituted by a tetranu-
clear complex (with or without TMA+; Supporting Informa-
tion, Table S5), which has an exo cavity nearly identical to that
of MOSC-1 but possesses no endo cavity.
À
lation revealed that the O H bond lengths of the m4-H2O
species were slightly longer than that of a free H2O molecule
by up to 0.086 ꢁ (Supporting Information, Figure S4b),
consistent with its proposed weak but substantial Brønsted
acidity.
A second experiment comparing the reactivity of malo-
nonitrile (2a) with that of Meldrumꢀs acid (2b) provided
additional mechanistic insights. 2b is known to be more acidic
than 2a (pKa = 7.3 vs. 11.1 in DMSO)[17] and thus represents
a generally better nucleophile than the latter. This was
evidenced by its higher reactivity with 1e (by more than
twice) when Me2L2, the dimethyl ester of H2L2, was used as
a small-molecule catalyst (Supporting Information, Table S4).
However, replacing Me2L2 with the supramolecular catalyst
MOSC-1 led to nearly 80% decrease for 2b but a more than
threefold increase for 2a in their respective reaction yield,
making 2b a significantly less effective nucleophile and
reversing the relative trend of reactivity. This interesting
finding is in line with the proposal that the Knoevenagel
The small amount of reduction of the overall yield for 1e
in the presence of TMA+ can be attributed to the cation
competing with the substrates for the limited nanospace of the
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MOSC endo cavity. Such a steric effect was even more evident
when TMA+ was replaced by a series of related cationic
regulators, such as tetraethylammonium (TEA+), tetrapropy-
lammonium (TPA+), and tetrabutylammonium (TBA+). The
increasingly larger size of the cations led to growing sterics
that effectively cancelled out the positive electrostatic effect
and resulted in a gradual decrease of the reaction yield
(Supporting Information, Figure S5). As indicated above,
a similar steric effect was also implicated in the MOSC-
catalyzed reaction involving 2b.
To further pinpoint how the tetraalkylammonium cations
interacted with the MOSC, we obtained MOSC-1’, an
isomeric structure to MOSC-1, by replacing CoII with ZnII
in the synthesis (see the Supporting Information). The
diamagnetic nature of MOSC-1’ allowed us to use the NMR
spectroscopy to probe the ammonium binding of the MOSC
in CDCl3. In the absence of a guest, the 1H NMR spectrum of
MOSC-1’ featured broad and poorly separated peaks (Sup-
porting Information, Figure S6), which we attributed to the
MOSC molecules aggregating in the solution. While adding
the aldehydes or 2a did not improve the spectrum, the
addition of an excess amount of TBA+ to the solution led to
a drastically simpler spectrum with well-defined peaks
(Figure 2). The protons of one equivalent of TBA+ underwent
their faster motion in and out of the endo cavity (Supporting
Information, Figures S9–S11).[20]
The validation of molecular recognition occurring at both
the endo and exo sites underscored the exciting potentials
afforded by the trademark multi-pore architecture of the
MOSCs, and begged the intriguing question of whether the
exo binding event also contributed to regulating the catalysis.
Comparing the kinetic profiles of the reactions involving 1e,
2a, MOSC-1, and 0–9 equivalents of TMA+ indicated that the
reactivity was strongly influenced by the amount of TMA+
added (Supporting Information, Figure S12). Since there is
only one equivalent of TMA+ residing inside the endo cavity,
and additional TMA+ equivalents must be located outside the
substrate binding pocket, this finding suggested that the
MOSC-based catalyst system likely employed an unconven-
tional allosteric mechanism, in which electrostatic interac-
tions, instead of, or in addition to, conformational changes,
were used to regulate the catalysis.[7a,21]
In short, we successfully utilized a new class of container
molecules to harvest several trademark features of enzymatic
catalysis. We made use of two particularly important ele-
ments, namely selective substrate recognition and electro-
static/allosteric regulation, to switch on supramolecular
catalysis. The ability to demonstrate such biomimetic charac-
teristics in synthetic and non-aqueous systems has profound
implications for designing highly functional, complex, and
modular enzyme mimics. In particular, the viability to employ
task-specific small-molecule regulators to modulate chemical
reactions is anticipated to afford unprecedented opportunities
in asymmetric catalysis, photocatalysis, and other related
areas.
Acknowledgements
This research was supported by a National Science Founda-
tion CAREER Award CHE-1352279. Z.W., Y.Q., and J.L.
also acknowledge an NSF MRI Award CHE-1229035 for the
purchase of a Bruker 400 MHz NMR spectrometer.
Figure 2. 1H NMR spectrum of TBA+@MOSC-1’ in CDCl3. The molar
ratio of TBA+:MOSC-1’ is ca. 6.
a significant upfield shift, indicating its encapsulation inside
the endo cavity. The much larger up-field shift of a-protons
(Dd ꢀ 2.02 ppm), compared with that of d-protons (Dd
ꢀ 0.26 ppm), suggested that the positive charge of TBA+
was located deeper inside the binding pocket than its alkyl
ends, consistent with the proposed electrostatic mechanism.
The 1:1 binding ratio was verified by the Jobꢀs plot based on
a UV/Vis study of MOSC-1 (Supporting Information, Fig-
ure S7). The endo-capsulation of TBA+ by the MOSC was
Keywords: calixarenes · container molecules ·
Knoevenagel condensation · supramolecular catalysis ·
tetraalkylammonium
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[20] D. L. Caulder, R. E. Powers, T. N. Parac, K. N. Raymond,
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Received: July 14, 2016
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Revised: August 8, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Supramolecular Catalysis
Switching on catalysis: A new class of
synthetic receptors exhibit enzyme-like
properties in organic solvents. Their
catalytic activity (see picture; green
arrow) can be turned on by a size and
shape match of the substrate with the
binding pocket. The electrostatic envi-
ronment of the active site can be further
modulated using cationic regulators
(blue arrow).
Y. Qiao, L. Zhang,* J. Li, W. Lin,*
Z. Wang*
&&&& — &&&&
Switching on Supramolecular Catalysis
via Cavity Mediation and Electrostatic
Regulation
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!